Core A Project Summary: The Principal Aim of Core A will be to support the Overarching Goal of this Program Project to identify small molecule and peptide Env gp120 inhibitors, defining their structural mechanisms of action by exploiting structure-mechanism correlations as a guide to optimize antagonist function. To this end, Core A will focus on the recent significant progress made by the Program Project in the development of small molecule and peptidomimetic viral entry antagonists, in conjunction with the emerging structural information of both gpl20 monomer and the Env trimer. We will focus on three Env interfaces that mediate HIV-1 infection. These are: (A) the highly conserved CD4-gp120 binding site; (B) the chemokine receptor-gp120 V3-loop interface; and (C) the gp41-interacfing element of gpl20. During the recent grant period Core A successfully guided cycles of design, synthesis and structure determination for gp 120 antagonists. Building on this success, we will continue to integrate with Crystallography (Hendrickson and Kwong), Virology (Sodroski), Peptide and Mini-proteins (Chaiken), Small Molecule Synthesis (Smith), Thermodynamics (Freire), and Single Molecule FRET (Mothes and Blanchard). Antagonists (peptides, small molecules and fragments) discovered and validated by these groups, will in turn be optimized computationally by Core A, and in collaboration with the Synthetic (Smith) and Peptide/Peptidomimetic Projects (Chaiken) advance novel small molecules and peptides for virological testing and validation (Sodroski).